In vivo generation of human CD19‐CAR T cells results in B‐cell depletion and signs of cytokine release syndrome
Abstract Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809158 |
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| Summary: | Abstract Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8‐LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B‐cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue‐invading CAR T cells and complete elimination of the B‐lymphocyte‐rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice. |
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| ISSN: | 1757-4676 1757-4684 |